Burimamide (IIa) was the first clinically effective histamine H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals, including man, but oral absorption is poor.
______________________________________ ##STR4## IIa; R = H, Z = CH.sub.2, X = S Burimamide b; R = CH.sub.3, Z = S, X = S Metiamide c; R = CH.sub.3, Z = S, X = NCN Cimetidine ______________________________________
Metiamide (IIb), a subsequently evaluated histamine H.sub.2 -antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an histamine H.sub.2 -antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug.
Reviews on the development of histamine H.sub.2 -antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al, Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976) and in references cited therein.
A large number of 2,5-disubstituted pyrimidone histamine H.sub.2 -receptor antagonists having the general formula: ##STR5## are known in the art. Thus, European Patent Application No. 4,793, published Oct. 17, 1979,; European Patent Application No. 3,677, published Aug. 22, 1979; European Patent Application No. 15,138, published Sept. 3, 1980; European Patent Application No. 24,873, published Mar. 11, 1981; European Patent Application No. 49,173, published Apr. 7, 1982; and World Patent Application No. 8,000,966, published May 15, 1980 disclose such compounds wherein R can be a group similar to the group substituted on the 2-amino group of the compounds disclosed and claimed herein and R.sup.1 can be hydrogen, alkyl or substituted alkyl. However, none of these applications disclose such compounds substituted at the 5-position with a nitro group or an amino group as is the case with the compounds disclosed and claimed herein.